Induction therapy with ipilimumab and nivolumab followed by consolidative chemoradiation as organ-sparing treatment in urothelial bladder cancer: study protocol of the INDIBLADE trial.

Introduction: Studies that assessed the efficacy of pre-operative immune checkpoint blockade (ICB) in locally advanced urothelial cancer of the bladder showed encouraging pathological complete response rates, suggesting that a bladder-sparing approach may be a viable option in a subset of patients. Chemoradiation is an alternative for radical cystectomy with similar oncological outcomes, but is still mainly used in selected patients with organ-confined tumors or patients ineligible to undergo radical cystectomy. We propose to sequentially administer ICB and chemoradiation to patients with (locally advanced) muscle-invasive bladder cancer. Methods: The INDIBLADE trial is an investigator-initiated, single-arm, multicenter phase 2 trial. Fifty patients with cT2-4aN0-2M0 urothelial bladder cancer will be treated with ipilimumab 3 mg/kg on day 1, ipilimumab 3 mg/kg plus nivolumab 1 mg/kg on day 22, and nivolumab 3 mg/kg on day 43 followed by chemoradiation. The primary endpoint is the bladder-intact event-free survival (BI-EFS). Events include: local or distant recurrence, salvage cystectomy, death and switch to platinum-based chemotherapy. We will also evaluate the potential of multiparametric magnetic resonance imaging of the bladder to identify non-responders, and we will assess the clearance of circulating tumor DNA as a biomarker for ICB treatment response. Discussion: This is the first trial in which the efficacy of induction combination ICB followed by chemoradiation is being evaluated to provide bladder-preservation in patients with (locally advanced) urothelial bladder cancer. Clinical Trial Registration: The INDIBLADE trial was registered on clinicaltrials.gov on January 21, 2022 (NCT05200988).

Occult lymph node metastases in patients without residual muscle-invasive bladder cancer at radical cystectomy with or without neoadjuvant chemotherapy: a nationwide study of 5417 patients.

PURPOSE: Little is known about the prevalence of occult lymph node metastases (LNM) in muscle-invasive bladder cancer (MIBC) patients with pathological downstaging of the primary tumor. We aimed to estimate the prevalence of occult LNM in patients without residual MIBC at radical cystectomy (RC) with or without neoadjuvant chemotherapy (NAC) or neoadjuvant radiotherapy (NAR), and to assess overall survival (OS). METHODS: Patients with cT2-T4aN0M0 urothelial MIBC who underwent RC plus pelvic lymph node dissection (PLND) with curative intent between January 1995-December 2013 (retrospective Netherlands Cancer Registry (NCR) cohort) and November 2017-October 2019 (prospective NCR-BlaZIB cohort (acronym in Dutch: BlaaskankerZorg In Beeld; in English: Insight into bladder cancer care)) were identified from the nationwide NCR. The prevalence of occult LNM was calculated and OS of patients with <(y)pT2N0 vs. <(y)pT2N+ disease was estimated by the Kaplan-Meier method. RESULTS: In total, 4657 patients from the NCR cohort and 760 patients from the NCR-BlaZIB cohort were included. Of 1374 patients downstaged to <(y)pT2, 4.3% (N = 59) had occult LNM 4.1% (N = 49) of patients with cT2-disease and 5.6% (N = 10) with cT3-4a-disease. This was 4.0% (N = 44) in patients without NAC or NAR, 4.5% (N = 10) in patients with NAC, and 13.5% (N = 5) in patients with NAR but number of patients treated with NAR and downstaged disease was small. The prevalence of <(y)pT2N+ disease was 4.2% (N = 48) in the NCR cohort and 4.6% (N = 11) in the NCR-BlaZIB cohort. For patients with <(y)pT2N+ and <(y)pT2N0, median OS was 3.5 years (95% CI 2.5-8.9) versus 12.9 years (95% CI 11.7-14.0), respectively. CONCLUSION: Occult LNM were found in 4.3% of patients with cT2-4aN0M0 MIBC with (near-) complete downstaging of the primary tumor following RC plus PLND. This was regardless of NAC or clinical T-stage. Patients with occult LNM showed considerable worse survival. These results can help in counseling patients for bladder-sparing treatments.

Nomogram Predicting Bladder Cancer-specific Mortality After Neoadjuvant Chemotherapy and Radical Cystectomy for Muscle-invasive Bladder Cancer: Results of an International Consortium.

BACKGROUND: Cisplatin-based neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) is associated with improved overall and cancer-specific survival. The post-NAC pathological stage has previously been reported to be a major determinant of outcome. OBJECTIVE: To develop a postoperative nomogram for survival based on pathological and clinical parameters from an international consortium. DESIGN, SETTING, AND PARTICIPANTS: Between 2000 and 2015, 1866 patients with MIBC were treated at 19 institutions in the USA, Canada, and Europe. Analysis was limited to 640 patients with adequate follow-up who had received three or more cycles of NAC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A nomogram for bladder cancer-specific mortality (BCSM) was developed by multivariable Cox regression analysis. Decision curve analysis was used to assess the model's clinical utility. RESULTS AND LIMITATIONS: A total of 640 patients were identified. Downstaging to non-MIBC (ypT1, ypTa, and ypTis) occurred in 271 patients (42 %), and 113 (17 %) achieved a complete response (ypT0N0). The 5-yr BCSM was 47.2 % (95 % confidence interval [CI]: 41.2-52.6 %). On multivariable analysis, covariates with a statistically significant association with BCSM were lymph node metastasis (hazard ratio [HR] 1.90 [95% CI: 1.4-2.6]; p < 0.001), positive surgical margins (HR 2.01 [95 % CI: 1.3-2.9]; p < 0.001), and pathological stage (with ypT0/Tis/Ta/T1 as reference: ypT2 [HR 2.77 {95 % CI: 1.7-4.6}; p < 0.001] and ypT3-4 [HR 5.9 {95 % CI: 3.8-9.3}; p < 0.001]). The area under the curve of the model predicting 5-yr BCSM after cross validation with 300 bootstraps was 75.4 % (95 % CI: 68.1-82.6 %). Decision curve analyses showed a modest net benefit for the use of the BCSM nomogram in the current cohort compared with the use of American Joint Committee on Cancer staging alone. Limitations include the retrospective study design and the lack of central pathology. CONCLUSIONS: We have developed and internally validated a nomogram predicting BCSM after NAC and radical cystectomy for MIBC. The nomogram will be useful for patient counseling and in the identification of patients at high risk for BCSM suitable for enrollment in clinical trials of adjuvant therapy. PATIENT SUMMARY: In this report, we looked at the outcomes of patients with muscle-invasive bladder cancer in a large multi-institutional population. We found that we can accurately predict death after radical surgical treatment in patients treated with chemotherapy before surgery. We conclude that the pathological report provides key factors for determining survival probability.

Epigenetic profiling demarcates molecular subtypes of muscle-invasive bladder cancer.

Muscle-invasive bladder cancer (MIBC) is a heterogeneous disease that often recurs despite aggressive treatment with neoadjuvant chemotherapy and (radical) cystectomy. Basal and luminal molecular subtypes have been identified that are linked to clinical characteristics and have differential sensitivities to chemotherapy. While it has been suggested that epigenetic mechanisms play a role in defining these subtypes, a thorough understanding of the biological mechanisms is lacking. This report details the first genome-wide analysis of histone methylation patterns of human primary bladder tumours by chromatin immunoprecipitations and next-generation sequencing (ChIP-seq). We profiled multiple histone marks: H3K27me3, a marker for repressed genes, and H3K4me1 and H3K4me3, which are indicators of active enhancers and active promoters. Integrated analysis of ChIP-seq data and RNA sequencing revealed that H3K4 mono-methylation demarcates MIBC subtypes, while no association was found for the other two histone modifications in relation to basal and luminal subtypes. Additionally, we identified differentially methylated H3K4me1 peaks in basal and luminal tumour samples, suggesting that active enhancers play a role in defining subtypes. Our study is the first analysis of histone modifications in primary bladder cancer tissue and provides an important resource for the bladder cancer community.

Prediction of early (30-day) and late (30-90-day) mortality after radical cystectomy in a comprehensive cancer centre over two decades.

BACKGROUND: Radical cystectomy (RC) is associated with substantial postoperative mortality. In this study, we analyzed early (30-day; 30 M) and late (30-90-day; 30-90 M) mortality after RC in a Dutch tertiary referral center and determined factors associated with 30 M, 30-90 M and 90-day mortality (90 M). PATIENTS AND METHODS: We identified 823 patients who underwent RC for bladder cancer in the Netherlands Cancer Institute between 1997 and 2017. Predictive factors for mortality were analyzed to identify patients with a higher mortality risk. Multivariate logistic regression analysis was performed to examine the influence of patient, surgical and histopathological variables on 30 M, 30-90 M and 90 M. RESULTS: Thirty-day mortality was 1.9% and 90 M was 6.0%. Multivariable analysis showed that age (OR 1.08, 95% CI 1.01-1.1, p = 0.002) and ASA 3-4 (OR 3.57, 95% CI 1.25-10.16, p = 0.002) were significant predictors of 30 M while higher ASA score (OR 2.9, 95% CI 1.31-6.5, p = 0.009) and higher pathological T stage (OR 8.8, 95% CI 1.9-40.4, p = 0.005) were associated with 30-90 M. Risk of 90 M was increased in patients with ASA 3-4 (OR 2.4, 95% CI 1.2-4.9, p = 0.01), pT3-4 (OR 3.1, 95% CI 1.27-7.57, p = 0.01) and positive LNs (OR 2.5, 95% CI 1.25-4.98, p = 0.009). CONCLUSIONS: Patient-related factors predicted 30 M whereas both patient-related and cancer-related factors predicted 30-90 M. This suggests that patient mix, i.e. patient- vs. cancer-related factors for 30 M and 30-90 M, should be taken into account if mortality rates are to be compared between hospitals.

Concomitant CIS on TURBT does not impact oncological outcomes in patients treated with neoadjuvant or induction chemotherapy followed by radical cystectomy.

BACKGROUND: Cisplatin-based neoadjuvant chemotherapy (NAC) for muscle invasive bladder cancer improves all-cause and cancer specific survival. We aimed to evaluate whether the detection of carcinoma in situ (CIS) at the time of initial transurethral resection of bladder tumor (TURBT) has an oncological impact on the response to NAC prior to radical cystectomy. PATIENTS AND METHODS: Patients were identified retrospectively from 19 centers who received at least three cycles of NAC or induction chemotherapy for cT2-T4aN0-3M0 urothelial carcinoma of the bladder followed by radical cystectomy between 2000 and 2013. The primary and secondary outcomes were pathological response and overall survival, respectively. Multivariable analysis was performed to determine the independent predictive value of CIS on these outcomes. RESULTS: Of 1213 patients included in the analysis, 21.8% had concomitant CIS. Baseline clinical and pathologic characteristics of the 'CIS' versus 'no-CIS' groups were similar. The pathological response did not differ between the two arms when response was defined as pT0N0 (17.9% with CIS vs 21.9% without CIS; p = 0.16) which may indicate that patients with CIS may be less sensitive to NAC or ≤ pT1N0 (42.8% with CIS vs 37.8% without CIS; p = 0.15). On Cox regression model for overall survival for the cN0 cohort, the presence of CIS was not associated with survival (HR 0.86 (95% CI 0.63-1.18; p = 0.35). The presence of LVI (HR 1.41, 95% CI 1.01-1.96; p = 0.04), hydronephrosis (HR 1.63, 95% CI 1.23-2.16; p = 0.001) and use of chemotherapy other than ddMVAC (HR 0.57, 95% CI 0.34-0.94; p = 0.03) were associated with shorter overall survival. For the whole cohort, the presence of CIS was also not associated with survival (HR 1.05 (95% CI 0.82-1.35; p = 0.70). CONCLUSION: In this multicenter, real-world cohort, CIS status at TURBT did not affect pathologic response to neoadjuvant or induction chemotherapy. This study is limited by its retrospective nature as well as variability in chemotherapy regimens and surveillance regimens.

Superior efficacy of neoadjuvant chemotherapy and radical cystectomy in cT3-4aN0M0 compared to cT2N0M0 bladder cancer.

In this study, we compared complete pathological downstaging (pCD, ≤(y)pT1N0) and overall survival (OS) in patients with cT2 versus cT3-4aN0M0 UC of the bladder undergoing radical cystectomy (RC) with or without neoadjuvant chemo- (NAC) or radiotherapy (NAR). A population-based sample of 5,517 patients, who underwent upfront RC versus NAC + RC or NAR + RC for cT2-4aN0M0 UC between 1995-2013, was identified from the Netherlands Cancer Registry. Data were retrieved from individual patient files and pathology reports. pCD-rates were compared using Chi-square tests and OS was estimated by Kaplan-Meier analyses. Multivariable analyses were conducted to determine odds (OR) and hazard ratios (HR) for pCD-status and OS, respectively. We included 4,504 (82%) patients with cT2 and 1,013 (18%) with cT3-4a UC. Median follow-up was 9.2 years. In cT2 UC, pCD-rate was 25% after upfront RC versus 43% (p < 0.001) and 33% (p = 0.130) after NAC + RC and NAR + RC, respectively. In cT3-4a UC, pCD-rate was 8% after upfront RC versus 37% (p < 0.001) and 16% (p = 0.281) after NAC + RC and NAR + RC, respectively. In cT2 UC, 5-year OS was 57% and 51% for NAC + RC and upfront RC, respectively (p = 0.135), whereas in cT3-4a UC, 5-year OS was 55% for NAC + RC versus 36% for upfront RC (p < 0.001). In multivariable analysis for OS, NAC was beneficial in cT3-4a UC (HR: 0.67, 95%CI 0.51-0.89) but not in cT2 UC (HR: 0.91, 95%CI 0.72-1.15). NAR did not influence OS. In conclusion, NAC + RC was associated with superior pCD compared to RC alone and NAR + RC. Superior OS for NAC + RC compared to RC alone was especially evident in cT3-4a disease.

Short-term outcome after cystectomy: comparison of early oral feeding in an enhanced recovery protocol and feeding using Bengmark nasojejunal tube.

PURPOSE: Cystectomy for bladder cancer is associated with a high risk of postoperative complications. Standardized perioperative protocols, such as enhanced recovery after surgery (ERAS) protocols, aim to improve postoperative outcome. Postoperative feeding strategies are an important part of these protocols. In this two-centre study, we compared complications and length of hospital stay (LOS) between an ERAS protocol with early oral nutrition and a protocol with early enteral feeding with a Bengmark nasojejunal tube. METHODS: We retrospectively reviewed 154 consecutive patients who underwent cystectomy for bladder cancer in two hospitals (Hospital A and B) between 2014 and 2016. Hospital A uses an ERAS protocol (n = 45), which encourages early introduction of an oral diet. Hospital B uses a fast-track protocol comprising feeding with a Bengmark nasojejunal tube (Bengmark-protocol, n = 109). LOS and complications according to Clavien classification were compared between protocols. RESULTS: Overall 30-day complication rates in the ERAS and Bengmark protocol were similar (64.4 and 67.0%, respectively; p = 0.463). The rate of postoperative ileus (POI) was significantly lower in the Bengmark protocol (11.9% vs. 34.4% in the ERAS protocol, p = 0.009). This association remained significant after adjustment for other variables (odds ratio 0.32, 95% confidence interval 0.11-0.96; p = 0.042). Median LOS did not differ significantly between protocols (10 days vs. 11 days in the ERAS and Bengmark protocols, respectively; p = 0.861). CONCLUSIONS: Early oral nutrition in Hospital A was well tolerated. However, the Bengmark protocol was superior with respect to occurrence of POI. A prospective study may clarify whether the lower rate of POI was due to the use of early nasojejunal tube feeding or other reasons.

FDG-PET/CT for response evaluation of invasive bladder cancer following neoadjuvant chemotherapy.

PURPOSE: We investigated the accuracy of FDG-PET/CT response identification following neoadjuvant or induction chemotherapy (NAIC) for invasive bladder cancer (BC) as to better select patients for radical cystectomy (RC). METHODS: Between 2010 and 2014, 37 cT1-4N1-3 BC patients received a FDG-PET/CT before and after NAIC followed by RC. Metabolic lymph node (LN) response was evaluated according to EORTC recommendations. Additionally, primary tumor response was evaluated for 23 patients by means of delayed pelvic imaging after forced diuresis. Gold standard was response on pathologic analysis of RC specimens. Response was defined as partial response (pPR, any pathologic downstaging) or complete response (pCR, 

Association Of Plasma And Urinary Mutant DNA With Clinical Outcomes In Muscle Invasive Bladder Cancer.

Muscle Invasive Bladder Cancer (MIBC) has a poor prognosis. Whilst patients can achieve a 6% improvement in overall survival with Neo-Adjuvant Chemotherapy (NAC), many do not respond. Body fluid mutant DNA (mutDNA) may allow non-invasive identification of treatment failure. We collected 248 liquid biopsy samples including plasma, cell pellet (UCP) and supernatant (USN) from spun urine, from 17 patients undergoing NAC. We assessed single nucleotide variants and copy number alterations in mutDNA using Tagged-Amplicon- and shallow Whole Genome- Sequencing. MutDNA was detected in 35.3%, 47.1% and 52.9% of pre-NAC plasma, UCP and USN samples respectively, and urine samples contained higher levels of mutDNA (p = <0.001). Longitudinal mutDNA demonstrated tumour evolution under the selective pressure of NAC e.g. in one case, urine analysis tracked two distinct clones with contrasting treatment sensitivity. Of note, persistence of mutDNA detection during NAC predicted disease recurrence (p = 0.003), emphasising its potential as an early biomarker for chemotherapy response.

Hypoxia Marker GLUT-1 (Glucose Transporter 1) is an Independent Prognostic Factor for Survival in Bladder Cancer Patients Treated with Radical Cystectomy.

BACKGROUND: Tumour hypoxia, which is frequent in many cancer types, is associated with treatment resistance and poor prognosis. The role of hypoxia in surgically treated bladder cancer (BC) is not well described. We studied the role of hypoxia in two independent series of urothelial bladder cancers treated with radical cystectomy. METHODS: 279 patients from the University Hospital Network (UHN), Toronto, Canada, and Turku University, Finland were studied. Hypoxia biomarkers (HIF1-α, CAIX, GLUT-1) and proliferation marker Ki-67 were analyzed with immunohistochemistry using defined tissue microarrays. Kaplan-Meier methods and Cox proportional hazards regression models were used to investigate prognostic role of the factors. RESULTS: In univariate analyses, strong GLUT-1 positivity and a high Ki-67 index were associated with poor survival. In multivariate model containing clinical prognostic variables, GLUT-1 was an independent prognostic factor associated with worse disease-specific survival (HR 2.9, 95% CI 0.7-12.6, Wald p = 0.15 in the Toronto cohort and HR 3.2, 95% CI 1.3-7.5, Wald p = 0.0085 in the Turku cohort). CONCLUSION: GLUT-1 is frequently upregulated and is an independent prognostic factor in surgically treated bladder cancer. Further studies are needed to evaluate the potential role of hypoxia-based and targeted therapies in hypoxic bladder tumours.

Tumor heterogeneity of fibroblast growth factor receptor 3 (FGFR3) mutations in invasive bladder cancer: implications for perioperative anti-FGFR3 treatment.

BACKGROUND: Fibroblast growth factor receptor 3 (FGFR3) is an actionable target in bladder cancer. Preclinical studies show that anti-FGFR3 treatment slows down tumor growth, suggesting that this tyrosine kinase receptor is a candidate for personalized bladder cancer treatment, particularly in patients with mutated FGFR3. We addressed tumor heterogeneity in a large multicenter, multi-laboratory study, as this may have significant impact on therapeutic response. PATIENTS AND METHODS: We evaluated possible FGFR3 heterogeneity by the PCR-SNaPshot method in the superficial and deep compartments of tumors obtained by transurethral resection (TUR, n = 61) and in radical cystectomy (RC, n = 614) specimens and corresponding cancer-positive lymph nodes (LN+, n = 201). RESULTS: We found FGFR3 mutations in 13/34 (38%) T1 and 8/27 (30%) ≥T2-TUR samples, with 100% concordance between superficial and deeper parts in T1-TUR samples. Of eight FGFR3 mutant ≥T2-TUR samples, only 4 (50%) displayed the mutation in the deeper part. We found 67/614 (11%) FGFR3 mutations in RC specimens. FGFR3 mutation was associated with pN0 (P < 0.001) at RC. In 10/201 (5%) LN+, an FGFR3 mutation was found, all concordant with the corresponding RC specimen. In the remaining 191 cases, RC and LN+ were both wild type. CONCLUSIONS: FGFR3 mutation status seems promising to guide decision-making on adjuvant anti-FGFR3 therapy as it appeared homogeneous in RC and LN+. Based on the results of TUR, the deep part of the tumor needs to be assessed if neoadjuvant anti-FGFR3 treatment is considered. We conclude that studies on the heterogeneity of actionable molecular targets should precede clinical trials with these drugs in the perioperative setting.

Response to induction chemotherapy and surgery in non-organ confined bladder cancer: a single institution experience.

AIM: To evaluate the outcome of patients with locally advanced muscle-invasive and/or lymph node positive bladder cancer treated with induction chemotherapy and additional surgery. METHODS: All patients who were treated with induction chemotherapy in our institution between 1990 and 2010, were retrospectively evaluated using an institutional database. Induction chemotherapy consisted of methotrexate, vinblastine, doxorubicin and cisplatin (MVAC), or a combination of gemcitabine with either cisplatin or carboplatin (GC). RESULTS: In total 152 patients were identified, with a mean age of 59 years (range 31-76). One hundred and seven patients (70.4%) received MVAC, 35 patients received GC (23.0%) and 10 patients received GC after initial treatment with MVAC (6.6%). Median follow-up was 68 months (range 4-187 months). Overall 125 patients (82.2%) underwent cystectomy, whereas 12 patients (7.9%) received radiotherapy. Fifteen patients had no local treatment. Median overall survival was 18 months (95%CI 15-23 months). In 37.5% of patients with complete clinical response, residual disease was found at surgery (positive predictive value, PPV 62.5%). Complete pathological response was seen in 26.3% of patients, with a 5 year overall survival (OS) estimate of 54% (39%-74%). For patients with persisting node positive disease after induction chemotherapy and surgery OS was significantly worse (p < 0.0001). CONCLUSIONS: Complete clinical and/or pathological response to induction chemotherapy results in a significant survival benefit. The accuracy of the current clinical response evaluation after induction chemotherapy is limited. Although surgery may be important for staging and prognostic purposes, its role is unclear in node positive disease after induction chemotherapy.

Differences in histopathological evaluation of standard lymph node dissections result in differences in nodal count but not in survival.

OBJECTIVE: To analyse whether the reported differences in nodal yield at pelvic lymph node dissection (PLND) for bladder cancer, between two hospitals, are reflected in the survival rates. PATIENTS AND METHODS: We assessed follow-up data of all 174 patients (mean age: 62.7, median follow-up: 3 years) who underwent PLND between 1 January 2007 and 31 December 2009 at two different hospitals. PLND was performed according to a standardized template by the same urologists for comparable bladder cancer patients. Mean number of reported lymph nodes was 16 at hospital A versus 28 at hospital B. We compared the overall survival (OS), disease-specific survival (DSS) and recurrence-free survival (RFS) between both cohorts and performed a multivariate analysis. RESULTS: The cumulative probability for 2-year OS, DSS and RFS for hospital A are 61, 64 and 54 %, versus 58, 58 and 53 % for hospital B, respectively. Kaplan-Meier survival curves did not reveal statistically significant differences between both groups (OS: p log-rank = 0.75, DSS: p log-rank = 0.56, and RFS: p log-rank = 0.80). Also after adjustment for pT stage and neoadjuvant chemotherapy, survival was not significantly different between hospital A and hospital B. CONCLUSION: Despite differences in lymph node yield in PLND specimens, this study reveals no significant differences in survival outcomes between both hospitals. Standardized histopathological methods should be agreed upon by pathologists before integrating nodal yield and subsequent lymph node density as indicators of the quality of surgery and as prognostic factors.

Standard lymph node dissection for bladder cancer: significant variability in the number of reported lymph nodes.

PURPOSE: We compared the nodal yield after histopathological examination of extended bilateral pelvic lymph node dissection specimens for bladder cancer at 2 hospitals. Surgery at each hospital was done by the same 4 staff urologists using a standardized extended bilateral pelvic lymph node dissection template. MATERIALS AND METHODS: All consecutive patients with bladder cancer who underwent extended bilateral pelvic lymph node dissection from January 1, 2007 to December 31, 2009 were included in this study. Specimens were sent for pathological evaluation in a minimum of 2 packages per side. At the 2 pathology departments specimens were processed according to institutional protocols. RESULTS: A total of 174 patients with a mean age of 62.7 years were included in analysis. At hospital 1 a mean of 16 lymph nodes were found after dissection vs a mean of 28 reported at hospital 2 (p <0.001). No significant differences were found in the number of tumor positive lymph nodes (p = 0.65). Mean lymph node density at hospitals 1 and 2 was 9.3% and 3.9%, respectively (p = 0.056). CONCLUSIONS: Despite equal anatomical clearance by the same experienced surgeons we report a statistically significant difference between 2 pathology departments where the number of lymph nodes was evaluated after extended bilateral pelvic lymph node dissection for bladder cancer. Unless standardized methods are agreed on by pathologists, the number of reported lymph nodes as an indicator of surgical quality and lymph node density as a prognostic factor should be used cautiously.

Value of tissue markers p27(kip1), MIB-1, and CD44s for the pre-operative prediction of tumour features in screen-detected prostate cancer.

The pre-operative prediction of prognostic tumour features in the radical prostatectomy specimen using routine clinicopathological variables remains limited. The present study evaluated the predictive value of the cell-cycle protein p27(kip1), the proliferation marker MIB-1, and the cell-adhesion protein CD44s, determined on the diagnostic needle biopsy of asymptomatic men screened for prostate cancer. Of 81 screen-detected prostate cancers, representative biopsy cores and matched radical prostatectomy specimens were immunohistochemically stained for these tissue markers. Conventional pre-operative and post-operative clinicopathological variables were assessed and cancers were divided according to a validated tumour classification model (potentially harmless, clinically significant). Low (<50%) p27(kip1) expression, high (> or = 10%) MIB-1 expression, and low (<25%) CD44s expression were considered adverse prognostic signs. Binary logistic regression analysis was performed to assess the most valuable predictors of clinically significant disease. An adverse prognostic immunostaining assessment on the biopsy was found in 10 (12.3%), 17 (21.0%), and 25 (30.9%) cases for p27(kip1), MIB-1, and CD44s, respectively. The concordance in tissue marker assessment between the biopsy specimen and matched radical prostatectomy specimens was low for all three. The positive predictive value (PPV) of p27(kip1) was 90.0%, remarkably higher than that of MIB-1 and CD44s (41.2% and 52.0%, respectively), indicating that a low radical prostatectomy p27(kip1) score is expected if the biopsy p27(kip1) score is low. Logistic regression analysis revealed that biopsy Gleason score (p<0.01) and p27(kip1) assessment (p<0.01) remained the only significant predictors of clinically significant disease. All cases with low p27(kip1) expression were found to have clinically significant disease after radical prostatectomy. The assessment of p27(kip1) in the biopsy specimen might thus assist in distinguishing between potentially aggressive and potentially non-aggressive disease in prostate cancer screening.

A phase II trial of methotrexate-human serum albumin (MTX-HSA) in patients with metastatic renal cell carcinoma who progressed under immunotherapy.

INTRODUCTION: Renal cell carcinoma (RCC) has a poor prognosis when metastasized to distant sites, although immunotherapy may offer a prolongation of survival in selected patient groups. Unfortunately, no treatment options remain when immunotherapy fails. In this phase IIa trial the tolerability and efficacy of the antifolate drug methotrexate-human serum albumin (MTX-HSA) were evaluated in patients with metastatic RCC who progressed after first-line immunotherapy. PATIENTS AND METHODS: A total of 17 patients started treatment, and 14 (12 men, 2 women) were evaluable for response according to the phase IIa Gehan design. Patients had had prior tumor nephrectomy, were in relatively good general condition, had no impairment of renal, liver or bone marrow function, and had progressive metastatic disease after treatment with interferon-alpha (IFN-alpha) with or without cis-retinoic acid (EORTC protocols 30951 and 30947). MTX-HSA was given once a week intravenously on an outpatient basis at a dose of 50 mg/m(2). The treatment interval was prolonged in those patients who had not yet recovered from previous toxicities. RESULTS: Toxicity was manageable, relatively mild to moderate and reversible in most cases. Grade 2/3 mucositis (10/17) and grade 3 elevated transaminase levels (4/17) were most frequent, and in only one patient was a grade 4 thrombocytopenia reported. Of three inevaluable patients, one discontinued treatment due to drug-related toxicities. The mean administration interval was 12.1 days, and 7 of 14 evaluable patients had treatment intervals of 1 or 2 weeks. No objective responses were seen, although eight patients had stable disease (stabilization >2 months) for up to 8 months (median 121 days). CONCLUSION: MTX-HSA was generally well tolerated and can be given on an outpatient basis, but no objective responses were seen in patients with metastatic RCC who had progressed after previous immunotherapy.

Microsatellite analysis--DNA test in urine competes with cystoscopy in follow-up of superficial bladder carcinoma: a phase II trial.

BACKGROUND: It has been shown that microsatellite analysis (MA) is able to detect bladder carcinoma in urine. Relatively small groups of patients often with high stage and grade disease were investigated. However, greater than 85% of cystoscopies are performed for follow-up of superficial bladder carcinoma. The authors evaluated this DNA-based method in a group of consecutive patients in follow-up after transurethral resection of superficial disease. METHODS: Matched blood and urine samples from 109 patients were obtained before cystoscopy and subjected to MA. The BTA stat test (Bard Diagnostic Sciences, Inc., Redmond, WA) and cytology were used for comparison. RESULTS: Sixteen patients were excluded: the DNA was of insufficient quality for 7 patients and leukocyte abundance rendered the result of MA unreliable for 9 patients. For the remaining 93 patients, MA detected 18 of the 24 recurrent tumors. The six undetected tumors were small pTaG1 lesions for which immediate surgery was not necessary. Conversely, 5 of 9 patients with a positive MA and a negative cystoscopy had a tumor recurrence within 6 months after urine collection. In contrast, a recurrence occurred in only 7 of 60 patients who were negative in both MA and cystoscopy (P = 0.006). The MA (74%) appeared more sensitive than the BTA stat test (56%) or urine cytology (22%). CONCLUSIONS: Microsatellite analysis is a DNA test in urine that reliably signals the presence of recurrent bladder carcinoma, sometimes even before cystoscopic evidence of the disease. This noninvasive diagnostic tool has the potential to replace cystoscopy in many cases. The authors' results warrant the need for randomized trials.